| First Author | Hagenstein J | Year | 2019 |
| Journal | J Am Soc Nephrol | Volume | 30 |
| Issue | 8 | Pages | 1439-1453 |
| PubMed ID | 31311828 | Mgi Jnum | J:294466 |
| Mgi Id | MGI:6456509 | Doi | 10.1681/ASN.2019020118 |
| Citation | Hagenstein J, et al. (2019) A Novel Role for IL-6 Receptor Classic Signaling: Induction of RORgammat(+)Foxp3(+) Tregs with Enhanced Suppressive Capacity. J Am Soc Nephrol 30(8):1439-1453 |
| abstractText | BACKGROUND: New therapies blocking the IL-6 receptor (IL-6R) have recently become available and are successfully being used to treat inflammatory diseases like arthritis. Whether IL-6 blockers may help patients with kidney inflammation currently remains unknown. METHODS: To learn more about the complex role of CD4(+) T cell-intrinsic IL-6R signaling, we induced nephrotoxic nephritis, a mouse model for crescentic GN, in mice lacking T cell-specific IL-6Ra. We used adoptive transfer experiments and studies in reporter mice to analyze immune responses and Treg subpopulations. RESULTS: Lack of IL-6Ra signaling in mouse CD4(+) T cells impaired the generation of proinflammatory Th17 cells, but surprisingly did not ameliorate the course of GN. In contrast, renal damage was significantly reduced by restricting IL-6Ra deficiency to T effector cells and excluding Tregs. Detailed studies of Tregs revealed unaltered IL-10 production despite IL-6Ra deficiency. However, in vivo and in vitro, IL-6Ra classic signaling induced RORgammat(+)Foxp3(+) double-positive Tregs (biTregs), which carry the trafficking receptor CCR6 and have potent immunoregulatory properties. Indeed, lack of IL-6Ra significantly reduced Treg in vitro suppressive capacity. Finally, adoptive transfer of T cells containing IL-6Ra(-/-) Tregs resulted in severe aggravation of GN in mice. CONCLUSIONS: Our data refine the old paradigm, that IL-6 enhances Th17 responses and suppresses Tregs. We here provide evidence that T cell-intrinsic IL-6Ra classic signaling indeed induces the generation of Th17 cells but at the same time highly immunosuppressive RORgammat(+) biTregs. These results advocate caution and indicate that IL-6-directed therapies for GN need to be cell-type specific. |
